Brugada Syndrome: Recognizing the ECG Patterns

Ami Sharad Joshi, DO, MBA, Hospitalist, Division of Internal Medicine, Cooper University Hospital, Camden, NJ; David Kleinman, MD, Cardiologist, Crozer Chester Medical Center, Chester, Pa

Published Online: September 7, 2007 - 10:37:36 AM (CDT)

Brugada syndrome is inherited through familial autosomal dominant transmission. Nevertheless, the majority of cases are sporadic. The main characteristic is the electrocardiographic Brugada pattern, consisting of ST-segment elevations in leads V₁ through V₃, as well as right bundle-branch block and T-wave inversion. Patients with this condition are at risk for a sudden cardiac death, despite having structurally normal hearts. Familiarity with the electrocardiographic pattern is therefore essential for correct diagnosis. An implantable cardioverter defibrillator is the treatment of choice for preventing sudden cardiac death in patients at high risk for this condition.

Brugada syndrome is one of several conditions that can cause sudden cardiac death in a patient with a structurally normal heart. Patients normally have a family history of sudden cardiac death at an early age or a personal history of syncope or aborted sudden cardiac death. Diagnosis is based on demonstration of the characteristic electrocardiographic patterns, caused by a mutation in the cardiac sodium channels.¹ Even patients who are asymptomatic when the electrocardiographic Brugada pattern is discovered are at risk for a sudden cardiac death.

Illustrative Case

A 66-year-old white man whose medical history included pulmonary emboli and multiple sclerosis presented to the hospital with bilateral chest pain. The pain was located in the lower anterior chest and was sharp, nonradiating, and increased in intensity with deep breathing. The patient did not have any dyspnea, diaphoresis, abdominal pain, or nausea or vomiting. He denied the use of tobacco, alcohol, or illicit drugs. His family history included coronary artery disease. He was taking levetiracetam, amantadine HCl (for multiple sclerosis), warfarin sodium (for pulmonary embolism), finasteride, and a potassium supplement.

Physical examination revealed: chest pain and spasms, along with weakness in his legs; blood pressure, 80/60 mm Hg, without pulsus paradoxus; pulse, 84 beats/min. Auscultation revealed a systolic murmur along the left sternal border, with a multicomponent pericardial rub heard throughout, as well as a possible diastolic murmur. The rest of the examination was within normal limits.

Laboratory studies showed: creatine kinase (CK), 149 U/L (which later decreased to 121 U/L); CK MB isoenzyme, 33.7 ng/mL (which decreased to 23.3 ng/mL); relative index (CK-MB mass/CK) of 22.6 (decreasing to 19.3); troponin were not detected. The other results were within normal limits. The electrocardiogram (ECG) demonstrated a classic Brugada pattern, with rSR' and a 3-mm ST elevation in leads V₁ through V₃ (Figure 1).

Figure 1— ECG demonstrating the Brugada pattern.

An echocardiogram demonstrated normal left ventricular and right ventricular functions, with mild aortic and tricuspid regurgitation. An overnight pulse oximetry showed only mild desaturation with supplemental oxygen. The patient was admitted to the hospital for chest pain evaluation, with a presumed diagnosis of pericarditis; he was treated accordingly.

Upon his release from the hospital, the patient was told to follow up on his Brugada-pattern ECG, to evaluate the likelihood of a diagnosis of a Brugada syndrome, which would potentially require placement of an implantable cardioverter defibrillator (ICD).

Familial Autosomal Dominant Condition

Brugada syndrome, which affects the cardiac sodium channel, was first identified in 1992 by Pedro and Josep Brugada.² It is inherited through familial autosomal dominant transmission. A mutation, thought to be found on the SCN5A gene,³ leads to a decreased sodium inflow current, thereby reducing the duration of the normal action potential and resulting in a less opposed and more prominent outward potassium current.⁴ About 18% to 30% of patients have SCN5A mutations.⁵ Despite the presumed inheritance and clustering of cases in families, about two thirds of patients have a sporadic distribution.⁶ The net effect is a reduction in the duration of the normal action potential in the right ventricular epicardium, but not in the endocardium.⁴

The change in current is responsible for the characteristic ECG abnormalities seen in patients with Brugada syndrome and the tendency toward "phase-2 reentry" of the action potential, which can trigger ventricular arrhythmias.⁴ Consequently, a shorter-than-normal epicardial action potential occurs, which can lead to ST-segment elevation in the right precordial leads and to malignant reentrant ventricular tachyarrhythmias on the ECG.^4,7

Brugada syndrome can occur in different populations but is most common in Southeast Asian men. In one study, up to 0.7% of the 14,000 Japanese participants had a Brugada-type ECG, and only 0.12% had the type 1 ECG pattern. ⁸ In a Finnish study, about 0.6% of 3000 young and middle-aged adults had Brugada type 2 or type 3 ECG pattern, and none had the diagnostic type 1 pattern.⁹ In one US teaching hospital, 52 (0.4%) of 12,000 noncardiac patients were found to have an ECG pattern consistent with Brugada syndrome.¹⁰

Syncope, sudden cardiac death
Syncope, nocturnal agonal respiration, and sudden cardiac death (not related to exercise) are the only presenting symptoms in patients with Brugada syndrome.⁵ Those who present with aborted sudden cardiac death are at a greater risk of a recurrent arrhythmic event (69% at 54 months of follow-up) than patients presenting with syncope (19% at 26 months of follow-up).¹¹ About 8% of asymptomatic patients with a Brugadalike ECG pattern will subsequently have a first arrhythmic event.¹¹ These cardiac arrhythmias typically occur during sleep and are therefore vagally mediated arrhythmias.⁵ Patients usually present in the third or fourth decade of life; just under 50% of patients have a family history of sudden cardiac death.⁵ In addition to ventricular arrhythmias, patients are also at a greater risk of atrial arrhythmias. In a study of 59 patients with Brugada syndrome and 31 controls, spontaneous atrial fibrillation occurred in 20% of the Brugada patients and in none of the controls.¹²

The 3 ECG patterns
Brugada syndrome has 3 different ECG patterns. The classic Brugada pattern (type 1) consists of ST-segment elevations that descend and have an upward T-wave inversion ("coved type") in leads V₁ through V₃ (Figure 2).¹³ Types 2 and 3 have "saddleback" ST-T waves, with descending ST segments and an upright T wave; in type 2, the T wave is also upright or biphasic. A slight prolongation of the QT interval in Brugada-type ECG may be observed in the right precordial leads, secondary to the prolongation of the action potential duration in the right ventricular epicardium.⁵ The Brugada ECG patterns can be differentiated from typical right bundle-branch block patterns by the absence of widened S waves.⁵

Figure 2— 12-lead ECG of a typical Brugada type 1 pattern. A terminal R' wave in lead V1, a convex curve or "coved- type" ST-segment elevation in leads V1 (0.3 mV) and V2 (0.4 mV), and "saddle-shaped-type" ST-segment elevation in lead V3 (0.2 mV) can be seen during sinus rhythm. Reprinted with permission from Matsuo K, Akahoshi M, Nakashima E, et al. The prevalence, incidence and prognostic value of the Brugada- type electrocardiogram. J Am Coll Cardiol. 2001;38:765-770. Copyright ? 2001. The American College of Cardiology Foundation.

The Brugada ECG patterns can be provoked by several medications, including⁵:

• Sodium channel blockers (eg, oral flecainide, ajmaline, or intravenous procainamide)
• Beta-blockers
• Tricyclic antidepressants.

The sodium channel blockers should be administered in a controlled setting, with access to cardiopulmonary resuscitation in the event of AV block or electromechanical dissociation.

Other precipitators of the Brugada ECG pattern include⁵:

• Alcohol/cocaine toxicity
• Fever
• Hypercalcemia
• Hyperkalemia (by causing inactivation of the cardiac sodium channel)
• Hypokalemia
• Increased alpha-adrenergic tone
• Pacing
• Vagal maneuvers.

Diagnostic Criteria

Establishing the diagnosis is difficult, since the Brugada-type ECG pattern is also associated with other conditions that do not place the patient at increased risk of sudden death.⁴ Therefore, the identification of a patient with Brugada syndrome requires a proper history that covers present illness, family and personal history, and medication use, as well as appropriate laboratory tests, such as cardiac biomarkers and comprehensive metabolic panel in addition to the ECG pattern characteristic of Brugada.

The differential diagnoses of the Brugada syndrome include:

• Anteroseptal myocardial infarction
• Drug intoxication
• Hypercalcemia
• Hyperkalemia resulting in inactivation of cardiac sodium channels
• Hypothermia
• Left ventricular hypertrophy
• Pericarditis
• Right bundle-branch block
• Right ventricular infarction.

In patients with unexplained seizures, syncope, or nocturnal agonal respiration who have a normal ECG, a drug challenge using a sodium channel blocker may unmask the characteristic Brugada ECG.⁵

The Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology published proposed diagnostic criteria for Brugada syndrome in 2002.¹³ The diagnosis of type 1 Brugada syndrome is based on the presence of type 1 ST elevation (coved type) in more than 1 right precordial lead (V₁ through V₃), with or without a sodium channel blocker, along with at least 1 of the following conditions:

• Documented ventricular fibrillation
• Electrophysiologic inducibility of ventricular tachycardia
• Family history of sudden cardiac death at age younger than 45 years
• Nocturnal agonal respiration
• Self-terminating polymorphic ventricular tachycardia
• Syncope
• Type 1 ST elevation in ECG of family members.

The diagnostic criteria for type 2 or 3 Brugada syndrome are ST elevation (≥1 mm in type 2 and <1 mm in type 3) in more than one right precordial lead, with conversion to a type 1 Brugada ECG after the administration of a sodium channel blocker. In addition, the patient must meet one of the criteria for type 1 Brugada syndrome.¹³

Asymptomatic Patients

The diagnostic significance of a Brugada ECG in asymptomatic individuals is controversial. A Northern European study published in 2004 showed that 0.61% of healthy 18- to 30-year-old men and 0.55% of healthy 40- to 60-year-old men had spontaneous type 2 or 3 Brugada ECG patterns.⁹ These men were all asymptomatic, and none had a family history of sudden cardiac death. This suggests that type 2 or 3 Brugada ECG could be a normal variant, especially in non-Asian patients and in those with no family history of sudden cardiac death, and therefore no further investigation may be required.¹⁴

The largest review of asymptomatic patients with a diagnostic type 1 ECG Brugada pattern and no history of cardiac arrest involved 547 patients; 423 were asymptomatic, and the remainder had a history of at least 1 episode of syncope.¹⁵ The ECG pattern was spontaneous in 71% of patients, and was elicited after administering an antiarrhythmic drug in the remainder. The risk of arrhythmia and sudden cardiac death was determined based on whether the ECG patterns were spontaneous or presented only after the administration of medications, and if ventricular tachyarrhythmia was induced on electrophysiologic testing.

Patients with a spontaneous type 1 ECG pattern were more likely to have induced arrhythmias on electrophysiologic testing. During the 2-year follow-up, patients with an inducible arrhythmia had a 6-fold higher rate of sudden cardiac death or ventricular fibrillation compared with noninducible patients. Those with a history of syncope had a 2.5-fold higher risk of sudden cardiac death or ventricular fibrillation than asymptomatic patients. Based on these results, the authors concluded that asymptomatic patients with a Brugada ECG pattern should undergo programmed ventricular stimulation to determine their prognosis.

Treatment

The only proven treatment for preventing sudden cardiac death in patients with Brugada syndrome is the placement of an ICD. A consensus statement endorsed by the Heart Rhythm Society and the European Heart Rhythm Association includes an algorithm for the use of ICDs in patients with, or suspected of having, Brugada syndrome, based on a spontaneous or a sodium channel blocker?induced type 1 ECG (Figure 3).⁵ Treatment varies according to whether or not the patient has symptoms.

Figure 3— Management of patients with spontaneous/drug-induced Brugada ECG Adapted with permission from Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Circulation. 2005;111:659-670. View Figure 3 in a larger size.

Patients who have been resuscitated from sudden cardiac death and who have a structurally normal heart should receive an ICD and then undergo additional evaluation to determine the exact cause of the arrhythmia. Patients who have had syncope, seizure, or nocturnal agonal respiration should have an ICD implanted if no extracardiac cause can be found. These first 2 groups should also undergo electrophysiologic testing for evaluation of supraventricular arrhythmias. Close follow-up is recommended if a clear extracardiac cause is identified, but electrophysiologic testing is not necessary in such patients.⁵

Treatment of asymptomatic patients with a spontaneous or drug-induced type 1 ECG is based on a family history. Those with a spontaneous type 1 ECG who have a family history of sudden cardiac death that was thought to be due to Brugada syndrome should undergo electrophysiologic testing to determine if they have inducible arrhythmias. If the electrophysiologic study is positive, an ICD is needed; if the results are negative, they should be followed closely.

Electrophysiologic testing should also be considered in patients with a spontaneous type 1 ECG and no family history of Brugada syndrome, and in those with a drug-induced type 1 ECG. Again, positive results favor ICD, and negative results favor close follow-up. Patients with drug-induced type 1 ECG and no family history of Brugada syndrome require no additional testing but should be followed closely.⁵

The European Society of Cardiology (ESC) Task Force on Sudden Cardiac Death recommends ICD placement for patients with a type 1 ECG if they have survived cardiac arrest, have a history of syncope, or have a family history of juvenile sudden cardiac death.¹⁶ The ESC does not recommend electrophysiologic testing, even for high-risk patients, because of conflicting data on the predictive accuracy of electrophysiologic testing for risk stratification.^3,17

Another area of controversy is the diagnostic value of drug-induced type 1 ECG patterns; both false-positive and false-negative responses have been reported. In one study, 16% of patients with right ventricular cardiomyopathy who did not have Brugada syndrome had characteristic ST elevations following sodium channel blockade.¹⁸ In another study, flecainide was given to patients presenting with a normal ECG, but who had a previous type 1 ECG. Some of the patients did convert back to the type 1 Brugada pattern, indicating that the sensitivity and reliability of the test is less than 100%.¹⁹

There are no proven drug treatments for preventing sudden cardiac death in patients with Brugada syndrome. The pharmacologic approach consists of an effort to rebalance the currents during the early phase of the right ventricular epicardial action potential in the hopes of limiting the action potential notch and/or restoring the action potential dome.⁵ Some evidence suggests that quinidine may be beneficial by blocking the transient outward current in the right ventricle that promotes ventricular tachycardia/ventricular fibrillation. In one study, only 3 of 25 Brugada syndrome patients had inducible ventricular tachycardia after quinidine treatment.²⁰

Investigational approaches for patients with Brugada syndrome who are at increased risk of sudden cardiac death include radiofrequency ablation to prevent ventricular premature beats that can trigger ventricular arrhythmias²¹ and pharmacotherapy aimed at decreasing ventricular arrhythmias, using agents such as cilostazol (Pletal), sotalol HCl (Betapace), or mexiletine HCl (Mexitil).²²

Conclusion

Brugada syndrome is an important cause of sudden cardiac death in patients with structurally normal hearts. The diagnosis is based on the history, physical examination, laboratory testing, and ECG patterns characteristic of Brugada syndrome. Some patients may require further electrophysiologic evaluation for inducible ventricular arrhythmias to determine if an ICD should be placed. Family members of patients with known Brugada syndrome should be evaluated to determine their risk for this condition.

Disclosure statement
Dr Kleinman is a consultant to Guidant. Dr Joshi has nothing to declare.

SELF-ASSESSMENT TEST

1. Which of the following patients is least likely to have Brugada syndrome?

1. A 40-year-old Japanese-American woman
2. A 40-year-old white man
3. A 50-year-old white man
4. A 70-year-old white man

2. All the following ECG features are characteristic of Brugada syndrome, except:

1. Coved-type ST-segment elevations in leads V₁ through V₃
2. Coved-type ST-segment elevations in leads V₄ through V₆
3. Saddleback ST-T waves
4. Biphasic T wave

3. Which statement about the features of Brugada syndrome is not true?

1. Cardiac arrhythmias usually occur during sleep
2. Patients with a history of aborted sudden cardiac death are at greater risk for recurrent arrhythmias than patients with a history of syncope
3. Asymptomatic patients are not at risk of sudden cardiac death
4. Both hypokalemia and hyperkalemia can provoke a Brugada ECG

4. All the following criteria are diagnostic of type 1 Brugada syndrome, except:

1. Documented ventricular fibrillation
2. Family history of sudden cardiac death before age 45
3. History of syncope
4. History of seizure

5. All these are indications for ICD placement in patients with Brugada syndrome, except:

1. Asymptomatic patient with positive family history and inducibility on electrophysiologic testing
2. Asymptomatic patient with a negative family history who has a spontaneous type 1 ECG and inducibility on electrophysiologic testing
3. Syncope without an extracardiac cause
4. Nocturnal agonal respiration with an extracardiac cause

(Answers at end of references list)

References

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Answers: 1. D; 2. B; 3. C; 4. D; 5. D.